We are characterizing the CNS phenotypes caused by elevated mtDNA mutation levels and relating these findings to age-related functional changes. Furthermore, we will investigate the affects of ischemic brain injury in these same mice. We have already documented change in cortical thickness and lamination patterns. There are also changes in oxidative energy production and mitochondrial function. These changes parallel cognitive and motor deficiencies in the mtDNA mutators. Drugs that upregulate mitochondrial function are being evaluated.